Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes.
| Title: | Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. |
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| Authors: | Elyahu Y; The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.; Zlotowski Neuroscience Center and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Hekselman I; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Eizenberg-Magar I; Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.; Berner O; The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.; Zlotowski Neuroscience Center and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Strominger I; The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.; Zlotowski Neuroscience Center and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Schiller M; Departments of Immunology and Neuroscience, Rappaport Faculty of Medicine, and the Integrated Cancer Center, Technion-Israel Institute of Technology, Haifa 3525422, Israel.; Mittal K; The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.; Zlotowski Neuroscience Center and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Nemirovsky A; The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.; Zlotowski Neuroscience Center and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Eremenko E; The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.; Zlotowski Neuroscience Center and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Vital A; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Simonovsky E; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Chalifa-Caspi V; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Friedman N; Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.; Yeger-Lotem E; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; Monsonego A; The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.; Zlotowski Neuroscience Center and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel. |
| Source: | Science advances [Sci Adv] 2019 Aug 21; Vol. 5 (8), pp. eaaw8330. Date of Electronic Publication: 2019 Aug 21 (Print Publication: 2019). |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: eCollection Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]- |
| MeSH Terms: | Immunomodulation* ; Phenotype*; Aging/*immunology ; Aging/*metabolism ; CD4-Positive T-Lymphocytes/*immunology ; CD4-Positive T-Lymphocytes/*metabolism; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Animals ; High-Throughput Nucleotide Sequencing ; Mice ; Sequence Analysis, RNA ; Single-Cell Analysis |
| Abstract: | Age-associated changes in CD4 T-cell functionality have been linked to chronic inflammation and decreased immunity. However, a detailed characterization of CD4 T cell phenotypes that could explain these dysregulated functional properties is lacking. We used single-cell RNA sequencing and multidimensional protein analyses to profile thousands of CD4 T cells obtained from young and old mice. We found that the landscape of CD4 T cell subsets differs markedly between young and old mice, such that three cell subsets-exhausted, cytotoxic, and activated regulatory T cells (aTregs)-appear rarely in young mice but gradually accumulate with age. Most unexpected were the extreme pro- and anti-inflammatory phenotypes of cytotoxic CD4 T cells and aTregs, respectively. These findings provide a comprehensive view of the dynamic reorganization of the CD4 T cell milieu with age and illuminate dominant subsets associated with chronic inflammation and immunity decline, suggesting new therapeutic avenues for age-related diseases. |
| References: | Nat Immunol. 2010 Oct;11(10):905-11. (PMID: 20802483); Nat Rev Mol Cell Biol. 2005 Oct;6(10):801-11. (PMID: 16314869); Nat Med. 2017 Feb;23(2):174-184. (PMID: 28092664); Nat Commun. 2019 Feb 27;10(1):963. (PMID: 30814501); Nat Methods. 2017 Nov;14(11):1083-1086. (PMID: 28991892); Front Immunol. 2013 May 10;4:107. (PMID: 23675374); Genome Biol. 2016 Feb 17;17:29. (PMID: 26887813); Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18333-8. (PMID: 19815516); Nat Commun. 2017 Jan 16;8:14049. (PMID: 28091601); Annu Rev Immunol. 2010;28:445-89. (PMID: 20192806); J Gerontol A Biol Sci Med Sci. 2014 Jun;69 Suppl 1:S4-9. (PMID: 24833586); Nat Med. 2012 Oct;18(10):1518-24. (PMID: 23023500); J Immunol. 2008 Oct 1;181(7):4832-9. (PMID: 18802087); Science. 2003 Nov 7;302(5647):1041-3. (PMID: 14605368); Nature. 2018 Jun;558(7710):454-459. (PMID: 29899446); Cell. 2017 Jun 1;169(6):1000-1011. (PMID: 28575665); Immunity. 2015 Feb 17;42(2):203-205. (PMID: 25692694); Nature. 1995 Oct 19;377(6550):639-42. (PMID: 7566177); Cell Immunol. 2009;258(2):188-96. (PMID: 19482268); Nat Commun. 2015 Apr 07;6:6702. (PMID: 25850032); Cell Res. 2017 Jan;27(1):109-118. (PMID: 27995907); Immunity. 2017 Mar 21;46(3):364-378. (PMID: 28329703); Cell. 2017 Sep 7;170(6):1096-1108.e13. (PMID: 28886380); Allergy Asthma Proc. 2001 May-Jun;22(3):133-7. (PMID: 11424873); Nat Commun. 2019 Oct 17;10(1):4706. (PMID: 31624246); Trends Immunol. 2017 Mar;38(3):181-193. (PMID: 28161189); Trends Immunol. 2016 Dec;37(12):866-876. (PMID: 27720177); Immunity. 2015 Feb 17;42(2):265-278. (PMID: 25680272); Infect Immun. 2017 Aug 18;85(9):. (PMID: 28630062); Front Immunol. 2017 Jan 23;8:19. (PMID: 28167943); Nat Immunol. 2013 Mar;14(3):281-9. (PMID: 23334788); Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15053-8. (PMID: 14657384); Front Immunol. 2017 Mar 22;8:283. (PMID: 28382033); Nature. 2018 Dec;564(7736):434-438. (PMID: 30542152); Immunity. 2008 Jan;28(1):29-39. (PMID: 18164222); Nat Biotechnol. 2018 Jun;36(5):411-420. (PMID: 29608179); Science. 2017 Mar 31;355(6332):1433-1436. (PMID: 28360329); Immunity. 2016 May 17;44(5):1005-19. (PMID: 27192566); Nat Med. 2019 Mar;25(3):487-495. (PMID: 30842675); Front Immunol. 2013 Nov 19;4:379. (PMID: 24312094); Nat Immunol. 2018 Jan;19(1):10-19. (PMID: 29242543); Nat Rev Immunol. 2015 Aug;15(8):486-99. (PMID: 26205583); Nat Med. 2018 Jul;24(7):978-985. (PMID: 29942094); Cell Death Differ. 2009 Feb;16(2):331-9. (PMID: 19008920); J Crohns Colitis. 2017 May 01;11(5):621-630. (PMID: 28453760); Curr Opin Immunol. 2009 Aug;21(4):414-7. (PMID: 19500967); PLoS One. 2015 Jul 27;10(7):e0127336. (PMID: 26214311); J Exp Med. 2010 Mar 15;207(3):637-50. (PMID: 20156971); Cell. 2018 May 31;173(6):1385-1397.e14. (PMID: 29706550); Arthritis Res Ther. 2017 Apr 26;19(1):79. (PMID: 28446208); Nat Immunol. 2018 Mar;19(3):291-301. (PMID: 29434354); J Immunol. 2014 Sep 15;193(6):2622-9. (PMID: 25193936); Nat Immunol. 2017 Mar;18(3):354-363. (PMID: 28114291); Annu Rev Immunol. 2013;31:259-83. (PMID: 23298210); Cell. 2017 Jun 15;169(7):1342-1356.e16. (PMID: 28622514); Nat Immunol. 2016 Apr;17(4):461-468. (PMID: 26878114); Nat Rev Immunol. 2012 Mar 16;12(4):306-15. (PMID: 22421787); Sci Immunol. 2018 Jan 19;3(19):. (PMID: 29352091); Nat Commun. 2014 Jun 24;2:4172. (PMID: 24960204); Nat Rev Mol Cell Biol. 2014 Jul;15(7):482-96. (PMID: 24954210); Nat Immunol. 2011 Apr;12(4):304-11. (PMID: 21378976) |
| Entry Date(s): | Date Created: 20190829 Date Completed: 20200507 Latest Revision: 20231013 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC6703865 |
| DOI: | 10.1126/sciadv.aaw8330 |
| PMID: | 31457092 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't